Genetic Dissection of a VIP Link between Immune Dysfunction and Neurodevelopmental Disorders Characterized by Social Deficits

免疫功能障碍与以社交缺陷为特征的神经发育障碍之间 VIP 联系的基因剖析

• 批准号: 10569057
• 负责人: Xiaohong Lu
• 金额: $ 22.05万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569057
• 关键词: Affect; Animal Model; Bacterial Artificial Chromosomes; Behavior; Behavioral; Birth; Blood; Brain; CREB1 gene; Cells; Centers of Research Excellence; Cognitive; Cognitive deficits; Copy Number Polymorphism; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Disease; Dissection; Enterobacteria phage P1 Cre recombinase; Equilibrium; Etiology; Flow Cytometry; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Transfer Techniques; Genes; Genetic; Genetic Predisposition to Disease; Health; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunology; Impairment; Interferon Type II; Ligands; Link; Literature; Luciferases; Lymphocyte; Mediating; Meningeal; Microglia; Modeling; Molecular; Mus; Neonatal; Neurodevelopmental Disorder; Pathogenicity; Pathologic Processes; Patients; Pattern; Population; Reporter; Reporting; Research; Resolution; Risk Factors; Role; Schizophrenia; Series; Shapes; Signal Transduction; Social Behavior; Social Interaction; Symptoms; T-Lymphocyte; Th2 Cells; Time; Transgenes; Transgenic Mice; Translating; Vasoactive Intestinal Peptide; Work; antagonist; autism spectrum disorder; autistic children; cell type; cytokine; design; designer receptors exclusively activated by designer drugs; genetic approach; genome wide association study; genome-wide; human model; individualized medicine; innovation; insight; mouse model; neural circuit; neurodevelopment; overexpression; pathogen; postnatal; remote control; response; small molecule; social; social deficits; success; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; vasoactive intestinal peptide 2 receptor

Project 1 Project Summary/Abstract Immune dysfunction has been extensively reported in the literature as a risk factor contributing to neurodevelopmental disorders characterized by social deficits, e.g., autism spectrum disorder (ASD) and schizophrenia. From an evolutionary perspective, for many millions of years, human behavior, especially sociality, has been shaped by two ancient battling forces: pathogens and the immune system. Sickness behavior or avoidance of social interaction in ASD could thus be viewed as an immune input into the brain to evade the spreading of the pathogens. Emerging research within the last decade starts to reveal that immune inputs (e.g., meningeal immunity) can indeed affect neural circuits. The critical questions remain unanswered include whether, when and how a dysfunctional immunity can cause neurodevelopmental disorders characterized by social deficits? Besides, whether the immune system can be therapeutically targeted to ameliorate social symptoms in autism and schizophrenia? Recently, several large-scale genome-wide association studies (GWAS) pinpointed a Copy Number Variation (CNV) at the chromosomal locus 7q36.6 that is highly represented in schizophrenia and autism, with all of the microduplications (triplications) occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). Importantly, VIPR2 ligand, vasoactive intestinal peptide (VIP) has been found almost tripled the normal level in the neonatal blood of children with autism. It has been well established that VIP/VIPR2 signaling modulates immunity and shifts the Th1/Th2 balance in favor of Th2 cells. All these genetic findings pinpoint a long-sought link between the social deficits and dysfunctional immunity consistently observed in neurodevelopmental disorders. To translate such a genetic vulnerability into a mechanistic and pathophysiologic insight, we have developed a series of conditional VIPR2 Bacterial Artificial Chromosome (BAC) transgenic mouse models of VIPR2 CNV. The conditional design of the BAC allows switching-off the transgene in desired spatial-temporal patterns, controlled by Cre recombinase, thus facilitating dissection of the inflicted cell populations. Genetically over-activated VIPR2 signaling elicits early postnatal microglial pruning deficits and manifests robust social deficits. Therefore, we propose the central hypothesis that over-activated VIP/VIPR2 signaling in T cells elicits abnormal immune transformation to disrupt social brain development and/or social behavior. The hypothesis will be examined in the following specific aims: Aim 1 will examine the potential pathogenic role of VIPR2 CNV in T cells to elicit systemic immune imbalance to disrupt early postnatal brain development. This aim represents the first to employ a chemogenetic approach with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) together with CREB-luciferase reporter transgenesis to remotely control T cell-type-specific Gαs GPCR/PKA signaling to determine whether VIPR2 driven Th2 preferential differentiation is sufficient to elicit social deficits and brain developmental deficits. Our proposed genetic interrogation in an etiology-relevant animal model will shift the paradigm of the field by providing for the first time unequivocal causal evidence to that a dysfunctional immunity is sufficient and necessary to disrupt brain development and/or to manifest social behavioral deficits. Given that there is no disease-modifying therapy for autism and schizophrenia, our results will have an important positive impact because they lay the groundwork to the idea of tailoring of treatments (e.g., small molecule VIPR2 antagonist) targeting T cell immunity for resolution of social symptoms, which is highly innovative, and with tremendous translational value.

项目 1 项目摘要/摘要 文献中普遍报道免疫功能障碍是导致以下疾病的危险因素： 以社交缺陷为特征的神经发育障碍，例如自闭症谱系障碍（ASD）和 从进化的角度来看，数百万年来，人类的行为尤其如此。 社会性是由两种古老的战斗力量塑造的：病原体和免疫系统。 因此，自闭症谱系障碍患者避免社交互动可以被视为大脑的一种免疫输入，以逃避 过去十年中的新兴研究开始揭示免疫输入（例如， 脑膜免疫）确实会影响神经回路，但尚未得到解答的关键问题包括： 免疫功能失调何时以及如何导致以社交为特征的神经发育障碍 此外，免疫系统是否可以通过治疗来改善社会症状？ 最近，几项大规模全基因组关联研究（GWAS）明确指出了自闭症和精神分裂症 染色体位点 7q36.6 处的拷贝数变异 (CNV) 在精神分裂症中高度表现 和自闭症，所有的微重复（三倍体）都发生在一个基因内：血管活性肠 重要的是，VIPR2配体血管活性肠肽(VIP)几乎已被发现。 已经证实，VIP/VIPR2 是自闭症儿童新生儿血液中正常水平的三倍。 信号传导调节免疫力并改变 Th1/Th2 平衡，有利于 Th2 细胞。 查明长期寻求的社会缺陷与免疫功能失调之间的联系 将这种遗传脆弱性转化为机制和病理生理学障碍。 洞察，我们开发了一系列有条件的VIPR2细菌人工染色体（BAC）转基因 VIPR2 CNV 的小鼠模型 BAC 的条件设计允许在需要时关闭转基因。 由 Cre 重组酶控制的时空模式，从而促进受损细胞的解剖 基因过度激活的 VIPR2 信号会引发出生后早期小胶质细胞修剪缺陷和 因此，我们提出了过度激活 VIP/VIPR2 的中心假设。 T 细胞中的信号传导引发异常的免疫转化，从而破坏社会性大脑发育和/或社会性 该假设将在以下具体目标中进行检验： 目标 1 将检验潜力。 VIPR2 CNV 在 T 细胞中的致病作用，引发系统免疫失衡，扰乱产后早期大脑 这一目标代表了第一个采用设计受体的化学遗传学方法。 独家激活设计药物 (DREADD) 与 CREB ​​荧光素酶报告基因转基因一起 远程控制 T 细胞类型特异性 Gαs GPCR/PKA 信号传导以确定 VIPR2 是否驱动 Th2 优先分化足以引发社交缺陷和大脑发育缺陷。 与病因相关的动物模型中的遗传询问将通过提供以下方法来改变该领域的范式： 首次明确的因果证据表明，免疫功能失调足以且有必要破坏 鉴于没有疾病缓解疗法，大脑发育和/或表现出社会行为缺陷。 对于自闭症和精神分裂症，我们的结果将产生重要的积极影响，因为它们奠定了基础 定制针对 T 细胞免疫的治疗方法（例如小分子 VIPR2 拮抗剂）的想法 解决社会症状，具有高度创新性，具有巨大的转化价值。